Submissions for variant NM_000051.4(ATM):c.6998C>A (p.Thr2333Lys)

dbSNP: rs150503164

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212056	SCV000149148	likely benign	not provided	2021-05-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26787654, 24413734, 21665257, 19781682, 24618431, 25186627, 29522266)
Ambry Genetics	RCV000115239	SCV000185041	likely benign	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079437	SCV000254140	likely benign	Ataxia-telangiectasia syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115239	SCV000910893	likely benign	Hereditary cancer-predisposing syndrome	2015-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201251	SCV001372353	likely benign	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6998C>A (p.Thr2333Lys) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251024 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.6998C>A has been reported in the literature in individuals affected with breast cancer, hepatoblastoma, colon adenocarcinoma, or primary ovarian insufficiency, all without strong evidence for causality (e.g., Tung_2015, Young_2016, Aguiar_2022, Heddar_2022, Piha-Paul_2024). Additionally, this variant has also been reported in at-least one patient with Ataxia Telangiectasia (AT) who was compound heterozygous for two other deletrious variants in the ATM gene (Micol_2011). Although the phase of this variant relative to either of the deleterious variants was not provided, this finding supports a benign impact for this variant. Taken together, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25186627, 26787654, 21665257, 35495172, 36099812, 39085400). ClinVar contains an entry for this variant (Variation ID: 127434). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001201251	SCV002064679	uncertain significance	not specified	2019-07-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115239	SCV002536842	likely benign	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000212056	SCV003916785	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	ATM: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492467	SCV004239427	likely benign	Breast and/or ovarian cancer	2022-09-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589573	SCV005084823	likely benign	Familial cancer of breast	2024-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843477	SCV002103139	uncertain significance	Hepatoblastoma		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004549567	SCV004727439	likely benign	ATM-related disorder	2020-11-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).